Phosphoramidate derivatives of nucleosides
Compounds of formula I: including any possible stereoisomers thereof, wherein: R 1 is hydrogen, —C(═O)R 6 or —C(═O)CHR 7 —NH 2 ; R 2 is hydrogen; or C 1 -C 6 alkyl or phenyl, either of which is optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 -alkenyl and C 1 -C 6 alkoxy, hydroxy or amino, or R 2 is naphtyl; or R 2 is indolyl, R 3 is hydrogen, C 1 -C 6 alkyl, benzyl; R 4 is hydrogen, C 1 -C 6 alkyl, benzyl; or R 3 and R 4 together with the carbon atom to which they are attached form C 3 -C 7 cycloalkyl; R 5 is C 1 -C 10 alkyl, C 3 -C 7 -cycloalkyl, benzyl, or phenyl, any of which being optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, amino, mono- and diC 1 -C 6 alkylamino; R 6 is C 1 -C 6 alkyl; R 7 is C 1 -C 6 alkyl; R 8 is hydrogen or halogen; or a pharmaceutically acceptable salt or solvate thereof are useful in the prophylaxis or treatment of HCV infections.
1. A compound the formula I:
or a stereoisomeric form thereof, wherein:
R 1 is hydrogen, —C(═O)R 6 or —C(═O)CHR 7 —NH 2 ;
R 2 is hydrogen; or C 1 -C 6 alkyl or phenyl, the latter being optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy and amino; or R 2 is naphtyl; or R 2 is indolyl;
R 3 is hydrogen, C 1 -C 6 alkyl, benzyl;
R 4 is hydrogen, C 1 -C 6 alkyl, benzyl; or
R 3 and R 4 together with the carbon atom to which they are attached form C 3 -C 7 cycloalkyl;
R 5 is C 1 -C 10 alkyl, optionally substituted with C 1 -C 6 alkoxy; or R 5 is C 3 -C 7 cycloalkyl; benzyl; or phenyl, optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, C 1 -C 6 alkoxy, amino, mono- and diC 1 -C 6 alkylamino;
R 6 is C 1 -C 6 alkyl;
R 7 is C 1 -C 6 alkyl;
R 8 is hydrogen or halogen;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R 1 is hydrogen.
3. A compound according to claim 1 , wherein R 2 is Phenyl optionally substituted with 1, 2 or 3 substituents independently selected from halo, C 1 -C 6 alkyl, and C 2 -C 4 alkenyl, or wherein R 2 is naphtyl.
4. A compound according to claim 1 , wherein R 3 is Hydrogen and R 4 is methyl or wherein R 3 is methyl and R 4 is hydrogen, or wherein R 3 and R 4 are both methyl.
5. A compound according to claim 1 , wherein R 5 is C 1 -C 10 alkyl, C 3-7 cycloalkyl; or benzyl.
6. A compound according to claim 1 , wherein R 8 is hydrogen.
7. A compound according to claim 1 , wherein R 3 is hydrogen or C 1 -C 6 alkyl, and R 4 is hydrogen or C 1 -C 6 alkyl.
8. A compound according to claim 1 , wherein R 1 is hydrogen; R 2 is hydrogen; —NH—C(R 3 )(R 4 )—CO— forms L-Ala or α,α-dimethylglycyl; R 5 is C 1 -C 8 alkyl, C 1 -C 4 alkyl substituted with C 1 -C 4 alkoxy, cyclopentyl, cyclohexyl, or benzyl; R 8 is hydrogen.
9. A compound according to claim 1 , wherein R 1 is hydrogen; R 2 is hydrogen; —NH—C(R 3 )(R 4 )—CO— forms L-Ala; R 5 is C 1 -C 8 alkyl, cyclopentyl, cyclohexyl, or benzyl; R 8 is hydrogen.
10. A compound according to claim 9 , wherein R 5 is cyclopentyl or cyclohexyl.
11. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition according to claim 11 , further comprising at least one additional HCV antiviral.